Analysis device and method

ABSTRACT

A point of use analyzer includes pump, valve, port, and storage channel. The storage channel may hold multiple assay packets composed of reagent aliquots separated by bounding slugs. The storage channel may define an elongated lumen having two ends with each of the ends coupled to the valve. A sampling device for use with the analyzer engages the port and may include a recurrent coaxial tube having a separation medium. A method of using the analyzer with the sampling device includes steps of pumping a fluid to displace a sample into the separation medium and out through the opposed connection.

This application is a continuation of PCT Application No.PCT/US14/25254, which claims priority to U.S. provisional applicationSer. No. 61/786,741 filed Mar. 15, 2013, the disclosure of which isincorporated by reference.

TECHNICAL FIELD

This invention relates to fluid handling in portable analyzers for pointof use analysis.

BACKGROUND ART

Fluid sample analysis, such as clinical sample analysis, involvesseveral operations that may be conducted with different frequencies. Forexample, an analyzer may run test analyses as needed. It may reloadreagents as materials are exhausted or expire. It may calibrateparticular assays as a reagent lot runs out or as operating conditionschange. An analyzer may run quality control specimens at fixedintervals.

An analyzer in a point of use environment may have widely varyingworkload. For example, in a physician's office, an analyzer might beidle much of the time. However, when a physician needs to determine apatient's condition, the physician may need or desire to know a fairnumber of analyte values while the patient is still present—a relativelyshort period of time. There is thus a need for an analysis system thatcan provide a number of measured values on a single sample within ashort time.

To be most useful, a point of use analyzer should be available whereverand whenever needed. This may require that the analyzer be operable whencarried, which in turn requires the analyzer to operate despite changesin orientation. The analyzer should be loadable with any necessaryreagents for determinations on multiple samples to support calibrationand quality control and to obviate cost of and need for the usercarrying separate analyte-specific consumable devices. There is thus aneed for an analysis system that can be preloaded with reagents and thatcan be stored and operated with changing orientation.

Use of an analyzer requires collection and preparation of samples.Traditional laboratory analysis collects large volumes of sample (as byvenipuncture) and processes the collected sample by centrifugation, arelatively slow process that uses bulky equipment. There is a need toprovide sampling devices that are compact and do not require bulkyequipment or time consuming manipulation.

DISCLOSURE OF INVENTION/SUMMARY

In some embodiments, the invention includes an analyzer comprisingfluidically connected pump, valve, port, and storage channel. The pump,port, and storage channel may be fluidically coupled to the valve. Thestorage channel may hold multiple assay packets composed of reagentaliquots separated by bounding slugs. The analyzer also includes acontroller such as a microprocessor that operates the valve and the pumpto form the assay packets. The storage channel may define an elongatedlumen having two ends.

The analyzer may receive a sample from a sampling device that engageswith the port so that the pump and valve can control the distribution ofsample. The analyzer forms a test packet by combining a portion of thesample with one of the assay packets. The analyzer can form a number ofsuch test packets, each including a portion of sample and an assaypacket, permitting analysis of a variety of analytes.

The analyzer may also include a vent fluidically coupled to the valve.The valve includes a common channel coupled to the pump so that the pumpmay be selectively engaged with the port and the storage channel bypositioning the valve to align the common channel with fluid connectionscoupled to the port or with one end of the storage channel. In someembodiments, the valve may include a second common channel fluidicallycoupled to a vent. The valve may be configured such that, when thecommon channel aligns with one end of the storage channel, the secondcommon channel aligns to the opposite end of the storage channel.

The analyzer may include multiple storage channels, each connected tothe valve and each containing a collection of assay packets or bulkreagents.

The valve may be a rotary shear valve that includes a stator havingsubstantially cylindrical cavity and a rotor disposed in the cavity.Both stator and rotor may include drive elements. The analyzer mayswitch the valve position by selectively activating one or more of thedrive elements.

The rotor may include a circumferential surface separated from thecylindrical wall of the cavity by a gap where the gap is configured toconfine an isolation fluid.

The sampling device may include a tube having connections at its endsand a separation medium within the tube lumen. A user adds a whole bloodspecimen to the loading end of the tube. The analyzer delivers adisplacement fluid to the loading end of the tube, pushing the bloodinto the separation medium and displacing part of the plasma out theopposite end.

In some embodiments, the analyzer delivers an aliquot of displacementfluid through the opposite end displacing a portion of the whole bloodspecimen out the loading end. The analyzer may dilute or subdivide thesample and associate the subdivisions with assay packets to form testpackets.

The sampling device may be configured as a recurrent tube, so that bothconnections are adjacent one another. Connections and the recurrent tubemay be coaxial. The tube lumen may be divided into a separatory regioncontaining the separation medium and a collection chamber adjacent theloading end. A flow isolator between the collection chamber and theseparatory region may hold the sample out of the separation medium sothat the analyzer can control separation timing for consistentoperation.

The sampling device may contain a reagent within the tube.

In some embodiments, the flow isolator includes a section of the flowchannel of larger diameter than the collection chamber or a section ofthe flow channel with a hydrophobic surface.

The sampling device may also include a retainer and identificationindicia on the external aspect of the tube.

A sample delivery method using the sampling device may includecontacting a specimen with the separation medium in the sampling device,introducing a displacement fluid from the first end, and displacing atleast a portion of the liquid component of the specimen from theseparation medium and through the second end. In some embodiments, themethod includes additional steps such as introducing a displacementfluid through the second end; and displacing at least a portion of thewhole blood specimen through the first end. The method may use any ofthe described embodiments of the sampling device including oneconfigured as a recurrent coaxial tube.

An analyzer may engage the connections of the sampling device and readany identification indicia. The engagement may include rotating thesampling device with respect to the analyzer and reading theidentification indicia. The analyzer may also advance the specimenacross the flow isolator into the separation medium.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a view of an embodiment of the fluid handling portion of aportable analyzer.

FIG. 2 shows a diagrammatic view of a portion of the fluids handlingsection of an embodiment of a portable analyzer.

FIG. 3 shows a view of the embodiment of FIG. 1 with a stator plate andassociated parts removed and reflected to show internal structure.

FIG. 4 shows a view of the embodiment of FIG. 1 with a valve rotor andassociated parts removed.

FIG. 5b shows a cross sectional view of the embodiment of FIG. 1 throughthe plane containing the line marked A-A on reference view FIG. 5 a.

FIG. 6 shows a view of the valve rotor removed from the embodiment ofFIG. 1.

FIG. 7 shows a partial diagrammatic cross sectional view of anembodiment of a valve.

FIG. 8a-d show multiple views of an embodiment of a sampling device.

FIG. 8e shows a cross sectional view of the sampling device of FIG. 8dthrough a plane containing the line A-A.

FIG. 8f shows an exploded view of the embodiment of a sampling device ofFIG. 8 d.

FIG. 9 shows a diagrammatic view of an embodiment of a storage channelcontaining assay packets.

FIG. 10 shows a block diagram of connection of the controller in anembodiment of the invention.

DETAILED DESCRIPTION

The analysis system may include major functional blocks of a basestation, a handheld analysis device (the analyzer), reagents, andsampling devices. A wirelessly-coupled external operator interfacedevice such as a phone or tablet computer may form another functionalblock.

The base station may be a tabletop scale device designed to prepare theanalyzer for use, such as that described in U.S. Pat. No. 7,431,883 toBell, the disclosure of which is incorporated by reference. In typicaloperation the user mounts the analyzer in the base station at intervals,such as once per day. The base station cooperates with the mountedanalyzer to perform a variety of preparative functions. These functionsinclude draining expended or expired materials from the analyzer;performing maintenance procedures such as rinsing fluid channels in theanalyzer; loading fresh reagents to the analyzer; calibrating theanalyzer and loaded assays; performing assays of quality controlmaterials; transferring information; and recharging the analyzerbatteries.

The analyzer is a device carried or held by a user so as to be availablefor assays whenever required. It contains on-board reagents necessary toperform any of a variety of assays. Because it may be hand held duringuse, its orientation may change in unpredictable ways. The analyzer mustmaintain its supply of reagents and perform analyses despite changes inorientation.

Reagents are materials, generally liquids or suspensions, which reactwith or support reactions with samples to detect or quantitate analytesof interest. Reagents also include materials to isolate, separate,rinse, dilute, or calibrate samples and reactions. Such reagents arewell known in clinical analysis.

Analyzer

Referring to FIGS. 1 and 2, the fluid handling portion 10 of theanalyzer includes a pump 12, a vent 14, a port 16, fluid channels (notvisible in FIG. 1, but disposed in manifold 110), a valve 20 and fluids(not shown). A sampling device 100 may be attached to the analyzer atport 16 during analysis. The analyzer also includes housing,electronics, and a power source such as a battery (not shown). While notillustrated, a controller, which may be a microcomputer or similarelectronic device, controls the operation of the various parts. Thediscussion that follows refers to operations performed by the analyzeror by a component of the analyzer. These references refer to control bythe controller as mediated by appropriate driver electronics andsoftware known in the art.

FIG. 2 illustrates fluidics diagrammatically. Closely spaced parallellines (such as storage channels 36) indicate fluid channels. The largerectangular elements each contacting multiple channels are parts of avalve 20 such as a linear shear valve or a rotary shear valve with itsswitching surface “unwound” to more clearly illustrate the multipleconnections. Each of rectangular elements 30 and 32 corresponds toconnections alignable with a single common channel. Valve 20 may includeonly a single common channel, in which case rectangular elements 30 and32 correspond to independent valves. Alternatively, a single valve mayhave more than one common channel, in which case the two illustratedrectangular elements 30 and 32 form part of a single valve with twocommon channels 230 and 234.

Pump

Pump 12 may be positive displacement pump such as a syringe pump or afixed seal piston pump. In some embodiments, the analyzer includes asecond pump 22 coupled to an analysis channel 34 and selectively coupledto pump 12 through a valve. Second pump 22 may alternately receive testpackets from pump 12 and drive received test packets through analysischannel 34 similarly to operations described in U.S. Pat. No. 5,399,497to Kumar et al., the disclosure of which is incorporated by reference. Atest packet comprises an assay packet (described below) and a samplealiquoted with the assay packet for analysis.

Vent

Vent 14 may be a connection to ambient air or to a plenum or to arelatively large capacity reservoir such as a waste chamber. In someembodiments, vent 14 includes a filter to prevent or limit aerosoldispersion.

Port

Port 16 is a connection point for adding or removing reactants to theanalyzer. At different times, port 16 may connect to an external devicesuch as a base station to replenish reagents and drain wastes, or asampling device 100 to receive samples for analysis. Port 16 includesone or more fluid connections 24 and 26. In some embodiments,connections 24 and 26 are coaxially arranged for ease of simultaneouscoupling to external devices.

Port 16 may be covered with a port seal 28 that closes port connections24 and 26 to prevent leakage when port 16 is not connected to anexternal device. Port seal 28 may also serve to interconnect portconnections 24 and 26 to allow washing or rinsing of port 16 andassociated channels and intersections 410-428. In some embodiments, portseal 28 may include an elastomeric cover with an opening such as a slitthat permits at least a portion of an external device to enter butcloses when no external device is present. Alternatively, port seal 28may include a sliding or inflatable component that the analyzer or userdeploys when external devices are removed.

Channels

The analyzer operates by moving fluids through channels. Channels areelongated cavities of small cross section relative to their length.Channels may comprise the lumens of extruded or molded tubes, such asfluorocarbon plastic tubing. Alternatively, channels may form part of amanifold within a substantially solid block of material. Manifoldchannels may be formed by machining, impressing, cutting, or moldingelongated trenches or voids in flat plates or foils and then bonding theplates or foils together, or by drilling holes in bulk material.Suitable plate materials include polymers such as acrylic plastic wherethe plates are diffusion bonded by commercially available processes suchas those offered by Eastern Plastics division of IDEX Corporation ofBristol, Conn. In some embodiments, plates may comprise substrates withhydrophobic surfaces including fluorocarbon plastics such as FEP or PFAor surface-treated acrylic. Fluorocarbon plastic plates may be bondedthermally or by metallization and controlled microwave exposure toselectively heat the plates at bonding surfaces. In other embodiments, amanifold incorporating channels and other features may be formed by anadditive manufacturing process.

In some embodiments, channels may comprise both manifold channels andchannels formed of extruded tubing. Such channels may be joined to oneanother using conventional couplings such as those manufactured byUpchurch Scientific division of IDEX Corporation of Oak Harbor, Wash.Alternatively manifold channels and extruded channels may be joined bypress fit, by plastics welding, or by similar methods.

Channels may be of any cross sectional shape, but round, half round, orsquare shapes limit the area of wetted channel surface and help reducecarryover between successive channel contents. When channels formed inpolymers with hydrophobic surfaces such as FEP are pre-wetted with anisolation liquid such as fluorocarbon liquid, the isolation liquid maypreferentially fill sharp edges or corners of channels producing menisciwith curved luminal surfaces that further reduce the surface area ofaqueous reactants in the channels. Such isolation liquids serve tofurther reduce carryover of successive aqueous channel contents.

Channels may be of any diameter consistent with the size of theanalyzer. Some channels may include regions of different diameters. Somechannels, such as channels holding waste fluids, may be of largediameter because waste fluids may freely intermix with one anotherwithout effect on analyzer operation. Channels holding other fluids,such as reactant storage and analysis channels described below, may beof relatively small diameter so that individual aliquots separated bybubbles span the channel diameter. Surface tension helps preventaliquots from mixing or bypassing one another when the analyzer changesorientation. Appropriate diameters for such channels depend on thenature of the channel wall material, the nature and presence ofisolation fluids, and the nature of the reactants. With FEP walls,fluorocarbon liquid isolation fluid, and aqueous reactants, anappropriate channel diameter is in the range of about 0.2 mm to about 2mm. In some embodiments, a channel diameter of about 1 mm is a goodcompromise between storage stability on orientation change and availablespace in a handheld analyzer.

Channels include analysis channels, storage channels, and operativechannels.

The analyzer includes one or more analysis channels. Analysis channelsmay include photometric analysis channels such as those described inKumar et al. Photometric analysis channels may include absorbance basedoptics and may also or alternatively detect fluorescent or luminescentlight. Analysis channels may include detectors, light sources, locallyincreased channel cross sections forming “vanish” features as in Kumaret al. to combine adjacent reactant aliquots, magnets to selectivelyretain or release magnetically susceptible particles or liquids, orother elements appropriate to a particular analysis. Analysis channelsmay include, for example, ion selective electrodes for measuring ionactivities or impedance sensors with a Coulter aperture for measuringand enumerating particles such as blood cells.

Storage Channels Store Fluids

Fluids include reactants, such as assay reagents and sample; systemfluids, such as displacement fluids, wash liquids, diluents, buffers,isolation fluids, and air; and expended materials. Storage channels 36may store or provide access to any of these fluids in undivided form.The analyzer may include a large number of storage channels. In someembodiments the analyzer includes from about 20 to 60 or more storagechannels.

Storage channels 36 may also or alternatively store reagents inpre-assembled packets so that a single storage channel 36 stores most orall non-sample components needed for multiple determinations of aparticular analyte. Each pre-assembled packet (an assay packet) containsprealiquoted reagents for a single determination. Assay packets mayinclude one or more measured volume reagent slugs separated by boundingslugs. Bounding slugs may also separate aliquoted sample slugs fromreagents in test packets. FIG. 9. illustrates diagrammatically a set ofassay packets disposed in storage channel 36. Reagent slugs 510 areseparated by smaller bounding slugs 520 within the lumen of storagechannel 36.

Bounding slugs comprise fluids substantially immiscible with reagents.Substantially immiscible fluids include liquids sparingly soluble in thereagent slugs. Where reagents are aqueous, substantially immisciblefluids include hydrophobic organic solvents, hydrocarbon and siliconoils, fluorocarbon liquids, and gases with limited aqueous solubilitysuch as air. In some embodiments, a fluid in a bounding slug may besubstantially immiscible with a reagent slug even though the fluid andthe reagent may be miscible when exposed to one another in bulk. Therelatively small contact area between reagent slug and bounding slug mayserve to limit significant mixing to near the point of contact. This isespecially effective when the reagent or the bounding fluid hasrelatively high viscosity, such as bounding fluids containing highconcentrations of methyl cellulose or glycerol.

The analyzer may include about 30 or more storage channels dedicated toanalyte-specific assay packets to accommodate a wide menu of tests. Eachstorage channel containing assay packets may include enough assaypackets for a full day of anticipated use. In some embodiments, eachstorage channel accommodates from about five to about 30 assay packets.About ten assay packets may be an appropriate capacity for manyapplications as this number fits in a reasonable length storage channeland is a reasonable match to clinical workloads. Multiple storagechannels may contain the same type of assay packets for high-useanalytes. Some storage channels may have more capacity than needed for aparticular analyte. The unused volume of such storage channels may beseparated from the assay packets by a bounding slug and filled with airor with a displacement fluid.

In some embodiments, a single storage channel 36 may store assay packetsfor more than one analyte. Such mixed storage is appropriate foranalytes frequently assayed on the same sample. For example, a singlestorage channel may contain assay packets for glucose, urea, andcreatinine arranged in sequential order as these three assays arecommonly run together as part of a basic metabolic panel.

A benefit of assay packet storage is that the analyzer or base stationmay set up at least a portion of an analytical reaction while the systemis otherwise idle. This advantageously allows launch of an assay in ashorter time than would be possible were assay packets formed as samplesarrive. By launching an assay in a shorter time, assays in progress maybe read more frequently, because photometric analysis channels mayoperate by alternately launching an assay and reading assays alreadylaunched. Shorter assay launch time thus reduces the time betweensuccessive assay reads. Fast successive reads provide a higher data ratethat more closely tracks rapidly developing photometric signals. Thehigher data rate permits use of faster reactions and hence a shortertime to result. A short time to result is particularly advantageous fora point of use analyzer because healthcare practitioners can use resultsduring a single patient interaction. This reduces diagnosis andtreatment delays improving outcomes and reducing costs.

The analyzer may set up assay packets by sequentially positioning valve12 at a position that aligns the pump with a channel containing a firstdesired constituent of an assay packet. Pump 12 then aspirates theselected amount of constituent. Analyzer repositions valve 20 to theposition of a channel containing the next constituent, and pump 12 againaspirates the requisite amount. One or more of the constituents may befluid (such as air) to form a bounding slug. This process continuesuntil a full assay packet, or a collection of multiple assay packets,are assembled sequentially in pump side valve common channel 230, inupper pass channel 274, and in its extension between the valve and thepump (marked as item 500 in FIG. 2) (collectively, the “pump-sidechannel”).

In a similar manner, the analyzer may set up test packets as needed oncea sample is available. The analyzer positions valve 20 at a positionthat aligns pump 12 with a storage channel containing the desired assaypackets. Pump 12 then aspirates an assay packet from that storagechannel into the pump-side channel and repositions the valve to alignwith a channel containing a bounding fluid, such as air. Pump 12 thenaspirates the desired volume of bounding fluid as a bounding slug intothe pump-side channel adjacent the aspirated assay packet. Analyzer thenpositions valve 20 at a position that aligns the pump with a channelcontaining sample. Pump 12 then aspirates the desired quantity of sampleinto the pump-side channel at a position adjacent the bounding slug. Ifneeded, an additional bounding slug may be added to the pump-sidechannel. The analyzer then aligns the valve with an analysis channel anddispenses the fully formed test packet to analysis channel 34.

In the above description, pump 12 connects to one end 40 of storagechannel 36 through the pump-side channel when valve 20 is appropriatelypositioned. The opposite end 38 of storage channel 36 connects throughlower common channel 234, lower pass channel 273, and extension of lowerpass channel (collectively, the “vent-side channel”) to reach vent 14.Pump 12 aspirates part of contents of storage channel 36 and transfersthat part to pump-side channel. Part of the content of vent-side channelmoves into storage channel 36 through opposite end 38 of storage channel36.

In some embodiments, the content of the vent-side channel is airdelivered through vent 14. In other embodiments, vent-side channel maybe prefilled with a displacement fluid, such as water or fluorocarbonliquid, so that the removed volume of storage channel 36 is replacedwith a relatively incompressible displacement fluid. This advantageouslyreduces the possibility of shifting of storage channel content andimproves subsequent dispense precision. To prefill the vent-sidechannel, valve 20 aligns with a storage channel containing theappropriate displacement fluid. Pump 12 dispenses a predetermined volumethrough pump-side channel so that a corresponding volume exits theopposite end of the selected storage channel and enters to prefill thevent-side channel. This prefill step would normally precede the transferof assay packets out of storage channel 36.

A second method by which vent-side channel may be prefilled uses pumpchannel 500, which may be loaded with a displacement fluid. Pump channel500 may continue beyond pump 12 to connect at its distal end to anaddressable location on the vent side of valve 20. Correspondingpump-side of valve 20 is unconnected (as indicated by the stubconnection in FIG. 2). When valve 20 is positioned so that vent-sidechannel of valve 20 aligns with the distal end of pump channel 500, thepump-side channel does not connect to a channel. With valve 20 thusaligned, aspiration by pump 12 transfers contents of pump channel 500 topump 12; dispense by pump 12 transfers contents of pump 12 to pumpchannel 500. While aspirating, the distal end of pump channel 500receives part of the content of vent-side channel. While dispensing, thedistal end of pump channel 500 delivers part of its content to vent-sidechannel.

The above described embodiment transfers assay packets by aspiratingwith pump 12. In other embodiments, pump 12 may transfer storage channelcontent by dispensing similarly to that described for the first prefilloperation. The skilled practitioner may apprehend the necessary plumbingchanges to effect this embodiment. The availability of displacementfluid in pump channel 500 allows pump 12 to be positioned at a desiredstroke position so that pump 12 may dispense displacement fluid to astorage channel.

Operative channels are a catchall category describing channels thatconnect between other locations, such as between pump and valve, betweenvent and valve, between valve and port, and between valve locations.These are described in more detail below.

Valve

The valve selectively couples channels to the pump and to the vent.Valves may comprise a cross point array or a network of three-wayswitching valves, but shear valves advantageously address fluidicconnections with clean fluid switching and minimal pumping action. Insome embodiments, the valve may be a rotary shear valve formed as arotor disk within a stator formed as a cylindrical cavity. The rotorincludes one or more common channels that may couple to the statorthrough rotary seals at or near the rotor axis. A 40 mm diameter rotorhas circumference of about 125 mm. With channels about one mm across,each common channel in such a rotor valve can address about forty eightchannels arranged about its circumference. Alternatively, the rotor canaddress channels disposed on a flat face of the stator cavity.

Construction of an embodiment of a rotary shear valve may be appreciatedby reference to FIGS. 3-6 where like parts bear the same item numbers.FIG. 3 shows a view of the stator cavity with the stator plate reflecteddownward to show interior detail. FIG. 4 shows a similar view with bothvalve rotor and stator plate removed. FIG. 5 shows a sectional view ofthe fluidics portion of the analyzer through the valve axis. Relativedirections, such as upper, lower, above, below, vertical, andhorizontal, in this description refer to the orientation with the outersurface of the rotor plate as the bottom.

Common channels may couple from stator to rotor through conventionalrotary seals such as O-rings or quad rings disposed axially betweenfaces of rotor and stator. Alternatively, common channels may couple tostator channels through segments of flexible tubing with the extent ofmovement of the rotor limited by software control to avoid twisting.

Rotary shear valve includes stator 202, rotor 204, bearings 226 and 228,and rotary seals 232 and 236.

Stator 202 comprises two pieces joined by fasteners, adhesives, welding,or interlocking geometry (not shown) to allow assembly. Manifold 110forms the upper portion and stator plate 260 forms the lower portion ofstator 202. Stator 202 defines a substantially cylindrical cavity 220between manifold 110 and stator plate 260.

Stator 202 includes embedded channels including pass channels andswitched channels. Upper and lower pass channels 274 and 276 align withthe rotor axis at opposite rotor faces. Pass channels pass fluids to therotor common channels via rotary seals. Switched channels terminate atthe cylindrical surface of stator 202. Switched channels include aplurality of upper switched channels (e.g. 238) that align in the planeof rotor upper common channel 230 and a plurality of lower switchedchannels (e.g. 240) that align in the plane of rotor lower commonchannel 234.

Rotor 204 comprises a cylindrical body 272 (best visible in FIG. 6) withopposed flat faces 212 and 214 and circumferentially disposed switchingsurface 270. Body 272 includes common channels and may include driveelements. Upper common channel 230 connects the center of upper rotorface 212 to switching surface 270. Lower common channel 234 connects thecenter of lower rotor face 214 to switching surface 270. FIGS. 3-6illustrate common channels 230 and 234 as radially aligned but commonchannels may be offset at an angle with respect to each other.

Rotor 204 is disposed within cavity 220. Cavity 220 includes uppercavity above rotor 204 and lower cavity below rotor 204.

Bearings comprising upper ball 226 and lower ball 228 support rotor 204shown disposed at a fixed height within cavity 220. Upper ball 226 andlower ball 228 may ride in circumferentially disposed V-grooves 278 inrotor 204. Bearings may include additional balls angularly disposedabout the rotor axis or may alternatively include sliding contactsurfaces or conventional annular bearings. In some embodiments, bearingsinclude three upper balls and three lower balls. Bearings may alsoinclude compliant members such as springs that bias any of upper ball226 and lower ball 228 against rotor 204.

O-ring 232 disposed between upper rotor face 212 and stator 202 acts asa rotary seal between upper common channel 230 and upper pass channel274. Lower common channel 234 connects to lower pass channel 276 viaO-ring 236 disposed between lower rotor face 214 and stator 202. Commonchannels 230 and 234 extend vertically from respective rotor facestoward the center plane of the cylinder forming body 272. Commonchannels 230 and 234 then continue as horizontal segments through rotor204 to switching surface 270. When positioned as in FIG. 5, rotor 204couples switched channels 238 and 240 through respective common channels230 and 234 to respective pass channels 274 and 276.

Pass channels connect to pump 12 and to vent 14 as visible in FIG. 2.Upper pass channel 274 may continue as pump side channel 500.

Rotation of rotor 204 selectively aligns the common channels to thedesired switched channels at a defined addressable position, therebyconnecting selected switched channels to the pass channels.

The analyzer may drive the rotor in a variety of ways. For example, therotor may couple axially to a motor shaft, either directly or throughgear teeth or pulley elements integral to or mounted coaxially with therotor axis.

In other embodiments, the shear valve rotor can form part of a motorarmature either by incorporating magnets, coils, or pole pieces. Therotor may contain both magnets and pole pieces to provide magneticreturn paths or to reduce cogging. Embedded magnets or pole pieces maybe sized and distributed within the rotor to avoid the common channel.Magnets, coils or pole pieces may be circular for ease of construction.Alternative coil and pole piece shapes, such as radially disposedtrapezoidal prisms, may increase torque and reduce cogging. Selectiveapplication of current to windings adjacent the rotor, such as above orbelow the rotor, produces a torque that drives the rotor to a newposition. The windings above and below may be angularly aligned toincrease torque or may be offset from one another to increase driveresolution. Sequential applications of current among the windings stepthe rotor to any addressable angular position. This process alignscommon channels with selected stator channels in a manner analogous todriving the armature of a stepper motor.

In some embodiments, the rotor may include four disk magnets 268 and thestator may include three windings above and three below the rotor. Eachrotor disk magnet may be retained in a conforming cavity of rotor 204.

Bearings may maintain the spacing between rotor and stator faces.Bearings may include balls recessed in stator faces and optionallyrunning within a groove in upper or lower rotor faces. Compliantelements such as springs may apply a seating force through bearings toone side of the rotor.

In the illustrated embodiment, both manifold 110 and stator plate 260include pockets 262 containing drive elements comprising coils 264surrounding cylindrical pole pieces 266. The drive elements in manifold110 and stator plate 260 are angularly offset from one another about therotor axis to increase drive resolution.

The valve switching process is under software control implemented by acontroller selectively applying current to coils 264. An encoder (notshown) may sense rotor position.

In some embodiments, the outside diameter of the rotor may closelyapproximate the inside diameter of a cylindrical cavity in the stator.Providing a narrow gap between these parts reduces friction making rotormotion easier and relaxing manufacturing tolerance requirements. The gapmay include an isolation fluid as a lubricant or as an aid in sealingthe valve from unwanted flow. Isolation fluid may be at least partiallyconfined to the gap by surface tension when the isolation fluid wets therotor and/or stator materials. FIG. 7 shows a partial diagrammaticsectional view of a portion of an embodiment of shear valve 300including stator 302, rotor 304, and gap 306 between rotor and stator.Rotor 304 includes two parallel common channels 330 and 334. The radialwidth of gap 306 is exaggerated to show detail. Isolation fluid 350within gap 306 is bounded by upper meniscus 308 and lower meniscus 310.The menisci form adjacent upper rotor surface 312 and lower rotorsurface 314 where the size of the void between rotor and statordramatically increases. FC 770 type of Fluorinert brand fluorocarbonliquid manufactured by 3M Company of St. Paul, Minn. sufficiently wetsFEP polymer that an open FEP tube of 1 mm diameter supports a column atleast 2 mm high. This degree of wetting is more than sufficient to filla gap between rotor and stator when the gap is less than 0.5 mmirrespective of orientation. Machining of FEP and similar materialsreasonably supports tolerances of 0.1 mm or less; FC 770 is thussuitable as an isolation fluid with gap widths within reasonable parttolerances.

Surface tension-based confinement of isolation fluid to a rotor-statorgap may be enhanced or augmented by inclusion of materials adjacent thegap that are not wettable by the isolation fluid. For example, where therotor and stator are fluorocarbon polymers such as FEP and the isolationfluid is a fluorocarbon liquid, opposing faces of the rotor near the gapmay include hydrophilic materials such as polyester as a covering filmor inlay. Alternatively, those faces may be treated by painting,coating, or selective plasma etching and chemical treatment. In otherembodiments, elastomeric seals such as O-rings may confine isolationfluid to the gap. In FIG. 7 first polyester film 316 covers acircumferential portion of upper rotor face 312. A second polyester film318 covers an analogous portion of lower rotor face 314.

Sampling Devices

Sampling devices provide samples to the analyzer. Sampling devices arenot part of the analyzer but removably connect to it through the port.In some embodiments, the sampling device includes a single-useconsumable that both prepares a sample and delivers the prepared sampleto the analyzer. The analysis system may include multiple types ofsampling devices that support different sample preparation methods. Forexample, sampling devices may include one of several anticoagulants whenthe sample is blood. Some types may separate cells from liquid sampleand other types may provide the sample as collected.

In some embodiments, a sampling device includes a fluid impermeablestructure defining an inlet, an outlet, and a channel extending betweenthe inlet and the outlet. Sampling devices may also include fluidconnections, mechanical connections, gripping attachments, closures, andmachine or human readable indicia.

The channel may extend as a straight lumen from one end of the samplingdevice to the other with inlet and outlet disposed at opposite ends.However, this linear configuration requires that a user seat connectionsat different ends of the device without touching either end. Otherpossible geometries include a tube that doubles back on itself so thatboth inlet and outlet of the channel are positioned at the same end ofthe sampling device. This permits a user to hold the device from one endwhile seating connections at the other.

The channel may include a vestibule, a portion of the channel adjacentthe inlet in which sample material is first deposited. The vestibule mayinclude surface properties and geometry configured to fill with anaqueous sample by capillary action. The vestibule may also includesample treatment materials such as anti-coagulant reagents.Anti-coagulants may be stored in either a wet or dry form. Dry materialshave advantages for shelf-life and handling. Anti-coagulants are wellknown and will not be further described. Other reagents, such asdiluent, lysing agents, or other pretreatment reagents may also oralternatively be present.

The portion of the channel closer to the outlet may include a separationmedium. The purpose of the separation medium is to separate blood cellsfrom liquid fractions of the blood. Many such separation media arecommercially available, including GE Healthcare's glass fiber sheetgrade VF2, Ahlstrom Corporation's Cytosep 1662 brand of plasmaseparation material, and others. Other separation materials may includesurface-bound materials that have an affinity for blood cells. Suchmaterials are generally available as thin sheets that may be cut,formed, or shredded and packed into a housing. Some samples, such aswhole blood for cellular analysis or urine, do not need separation ofcells to be analyzed. Embodiments of some sampling devices may thereforenot include separation materials.

The separation medium may also contain reagents such as anticoagulantsor clot accelerants.

Some embodiments of sampling devices include an isolator in a portion ofthe channel between the vestibule and the separation medium, if present.The purpose of the isolator is to help ensure uniformity of sampleprocessing. The isolator prevents the sample from entering the portionof the sampling device beyond the vestibule. This may be useful, forexample, when whole blood specimens are prevented from entering a bloodseparation medium until acted on by the analyzer. This assures that allseparated samples spend similar amounts of times in the separationmedium. This may reduce the possibility of cell lysis or of undesiredloss of sample constituents from a prolonged exposure to separationmaterials.

In some embodiments, the isolator prevents movement of samples bysurface properties and geometry. Where a hydrophilic surface materialwill actively wick aqueous samples, hydrophobic materials supportwicking to a much lesser extent and may repel aqueous materials. Thus anisolator may include a transition of material within the channel fromlesser hydrophobicity to greater. Alternatively, or in addition, thediameter of the channel may increase in the region of the isolator toprevent further sample travel absent a driving force or pressure.

Fluid connections couple sampling devices to the analyzer, but must alsoaccommodate loading of sample to the sampling device. Taperedconnections similar in principle to Luer style couplings and fittingscommonly used in syringes, needles, infusion equipment, and similardevices, allow two parts to form a removable fluid tight connection andmay be used as either or both connections on sampling devices. Inclusionof multi-start threads in such connectors make connection possible witha simple twist. Alternative connections may include face seals. Someembodiments may include both these two types of connections.

An embodiment of a sampling device appears in FIG. 8a-f . Thisembodiment 100 includes a core portion 120 and a sheath portion 140,both formed of fluid impervious plastic. Core portion 120 is a tubularpart with core wall 121 defining a lumen 122. Upper end 123 of coreportion 120 includes a taper connection 124 with about a 6% linear taperto connect to the analyzer. Lower end 125 includes castellated apertures126. The boundary of lumen 122 at upper end 123 includes a gentle radiusto make it easier for user to load a sample into lumen 122. Lumen 122may include internal divisions (not shown) to help a sample wick intolumen 122 and to draw sample away from the tip at upper end 123 so thatmore sample may be added. Part way down lumen 122 is isolator 127.Isolator 127 includes a segment of lumen 122 of increased internaldiameter. As discussed above, isolator 127 may serve to prevent samplefrom entering separation medium at an uncontrolled time. Isolator 127may also include a segment of more hydrophobic material, such as alength of FEP tubing (not illustrated) disposed adjacent lower end 125.

Sheath portion 140 is generally cup-shaped and includes base 141,cylindrical sheath wall 142, and outer connection 143 disposed at theend of sheath portion opposite base 141. The outer aspect of sheathportion 140 includes grip elements 144, label recess 145, and threadtabs 146.

Base 141 includes features designed to attach to lower end 125 of coreportion 120 so that core portion 120 may be inserted into sheath portion140 to form a single assembly. The parts may join by inference fit, byadhesive or solvent bonding, or by similar methods. Apertures 126 inlower end 125 extend upward from lower end such that, when core portion120 is seated in sheath portion 140, a flow path remains connectinglumen 122 through the unobstructed portion of apertures 126 into thespace between the outer surface of the core wall 121 of core portion 120and the inner surface of sheath wall 142 of sheath portion 140. Thisflow path continues to outer connection 143.

Outer connection 143 includes face seal 147 disposed on the extreme endsurface of sheath portion 140. A gap remains between sheath wall 142 andthe overhanging portion of taper connection 124. The flow path continuesthrough this gap when sampling device connects to analyzer at port 16.When assembled in this manner, core portion 120 and sheath portion 140form a recurrent tube with both ends of the tube disposed on the sameend of the assembly. This permits both fluid connections to connect tothe analyzer by holding the assembly from one end and advancing theassembly into the analyzer. As used herein, recurrent means turning backso as to reverse direction. The coaxial tube as described here isrecurrent. A “U-shaped” tube with ends disposed side by side is also arecurrent tube.

Analyzer port 16 includes mating receptacle connections 24 and 26complementary to sampling device taper connection 124 and outerconnection 143. The dimensions are designed so that, with allowance formanufacturing tolerances, taper connection 124 will seal to mating taperreceptacle 24 after face seal 147 contacts face of mating facereceptacle 26. This compresses face seal 147 against mating facereceptacle 26 as taper connection 124 seats into mating taper receptacle24, and assures that both connections are fluid tight.

Analyzer port 16 also includes a multi-start thread surrounding taperreceptacle 24 that is complementary to thread tabs 146 on upper aspectof outside of sheath wall 142. Thus sampling device 100 may be engagedwith analyzer port 16 by inserting taper connection 124 into matingtaper receptacle 24, engaging thread tabs 146 with complementary threadsof port 16, and twisting sampling device into sealing relationship witha single motion. Thread tabs 146 may also serve to secure a cap (notillustrated) to sampling device 100 prior to use to preserve the deviceand after use to contain sample wastes.

Grip elements 144 aid in this process by allowing a user to firmly graspand twist sampling device 100 into port 16. These may be a plurality ofraised bosses parallel to the axis of sampling device 100, but a varietyof shapes and designs are possible.

A portion of the exterior surface of sheath wall 142 above grip elements144 and below thread tabs 146 includes an indented label recess 145 toaccommodate a label (not shown). A label placed in label recess 145 maybe read by a user to identify information about sampling device 100,such as the type of sampling device, lot number, expiration date, andanti-coagulant. Such information may also be color coded by combinationsof colors for sheath portion 140 and core portion 120. A label withinlabel recess 145 may also contain machine readable information such as abar code or areal code. Such a code may be read during the insertionprocess as sampling device 100 rotates with respect to port 16 duringinsertion.

Sampling device 100 may also include separator 150 disposed in the spacebetween the outer aspect of core wall 121 and the inner aspect of sheathwall 142. In some embodiments, separator 150 may include fibersmacerated and inserted into sampling device 100. In other embodiments,separator 150 may include spirally wound sheet stock. A sheet separationmedium may be cut into a strip and wrapped around core wall 121 beforeassembly of core portion 120 to sheath portion 140. Commercialseparation material 0.3 mm thick may be wound about four times aroundcore wall 121 and around already wound layers of separation medium. Forease of assembly, the wound separation medium may be covered with asection of compliant tubing or with a section of thin-walled heatshrinkable tubing.

Commercial separation media include depth filters, membrane filters, orhybrid filters. Membrane filters efficiently block all blood cell frompassing but clog quickly. Depth filters allow blood cells to penetratesome distance into the medium before eventually entrapping them. Depthfilters may allow some cells to escape. Hybrid materials include someaspects of both types. It may be advantageous to include in separator150 a depth filter spirally wound as discussed with a section ofmembrane or hybrid filter proximate outer connection 143 to stop anyremaining cells.

FIG. 8e shows a cross section of the sampling device of this embodimentrevealing the position of separator 150 between core wall 121 and sheathwall 142. The structure is also visible in exploded view of FIG. 8 f.

Sampling Process

The sampling process is best understood by reference to FIG. 2. Pump 12connects through first valve side 32 of valve 20 to a selected channelat a selected addressable valve position indicated by item numbers tothe right of the second valve side 30. When aligned in a labeledposition (such as position 430), valve 20 connects pump 12 to thechannel (here channel 410) attached to valve side 32 in line with thelabeled position. Valve 20 also connects vent 14 to the channel (channel414) attached to valve side 32 in line with the labeled position.

Conduits related to the sampling process include sampling device 100,port connection 24 coupled to sampling device outer connection 143, andport connection 26 coupled to sampling device taper connection 124.Three channels branch from each of the port connections 24 and 26. Ashort channel (unlabeled) extends from port connection 24 to firstbranchpoint 426. Beyond first branchpoint 426, channel 420 reachessecond branchpoint 428 and then continues to connect to valve vent sideat position 440. Beyond second branchpoint 428, channel 422 extends tovalve vent side at position 460. Channel 424 continues as the otherbranch past first branchpoint 426 and connects to valve pump side atposition 460.

A short channel (unlabeled) extends from port connection 26 to thirdbranchpoint 416. Beyond third branchpoint 416, channel 410 extends pastfourth branchpoint 418 and connects to valve pump side at position 430.Channel 414 continues as the other branch past third branchpoint 416until reaching valve vent side at position 430. Beyond fourthbranchpoint 418, channel 412 extends to valve pump side at position 440.

Thus there are three channels from each connection of sampling device100. Two channels from the loading side of sampling device 100 (taperconnection 124) extend to the pump side of the valve; the remainingchannel extends to the vent side of the valve. Channels from theopposite side of sampling device 100 (outer connection 143) have thereverse distribution—two extend to the vent side of the valve and thethird extends to the pump side.

In operation, a user loads a sample, such as a fingerstick capillaryblood sample, into lumen 122 through the opening in taper connection124. Sample may be loaded directly from an expressed fingerstick dropletor through a collection capillary or similar device. User may also oralternatively transfer a bulk sample, as from a venous draw or urinecup, into lumen 122. User then loads sampling device 100 through portseal 28 into analyzer port 16 by twisting and advancing the part.

Analyzer may read information relevant to processing as sampling device100 seats into port 16. Analyzer may also vary the sampling processbased upon the read information. For example, if the read informationindicates that sampling device is of a type that does not include aseparator, analyzer may select air as a separation fluid to reduce thepossibility of sample dilution.

A first embodiment of a sample process loads a separated sample (such asplasma) into the analyzer. Once sampling device 100 is seated, analyzerpositions valve 20 at position 440 and pumps a displacement fluidthrough channel 412 and into taper connection 124. Displacement fluidmay be air, saline, or a viscous aqueous solution such asglycerol-saline. Displacement fluid pressure forces blood beyondisolator 127 and into separator 150. Blood wicks into separator undercapillary action (and optionally with additional displacement flow orpressure). After a suitable time for separator to trap blood cells (30seconds to 2 minutes depending on geometry and volume), analyzer pumpsfurther displacement fluid into sampling device 100, pushing plasmaahead of the front of displacement fluid and out through outerconnection 143, through port connection 24, and into channel 420.Continued pumping moves the plasma front beyond first branchpoint 426and thence up channel 420 to second branchpoint 428. Plasma front enterschannel 420 because channel 420 connects to vent 14 via valve vent side30. No other connected channel can accommodate significant flow becausenone are vented when valve is positioned at position 440.

Once the plasma front passes a predetermined distance beyond firstbranchpoint 426 (or alternatively, after plasma front passes secondbranchpoint 428), analyzer positions valve 20 at position 460 andaspirates separated sample through channel 424 into the channelconnected to pump 12 for storage or processing. Pump 12 may then rinseany channels that had been wetted by fluid in preparation for furtheractions.

A second embodiment of the sample process combines the transfer of aportion of whole blood (for cellular analysis or for other analytesrequiring cells, such as glycated hemoglobin). Analyzer positions valve20 at position 440 and aspirates whole blood past third branchpoint 416.Analyzer then positions valve 20 at position 430 and aspirates wholeblood from the segment of channel 410 beyond third branchpoint 416 intothe channel connected to pump 12 for storage or processing. Pump 12 maythen rinse any channels that had been wetted by fluid in preparation forfurther actions.

After removing an aliquot of whole blood, analyzer may then collectplasma by performing the first recited process. Thus with a singlesampler, analyzer may collect both whole blood and liquid sample (plasmaor serum) and perform a wide range of analyses.

The provision of channel geometry having multiple branch points andmultiple valve positions coupled to the channels allows a variety ofchoices of sample handling sequences that combine features or conceptsof the above embodiments. A skilled practitioner may apprehendalternative processes based on this geometry that produce similarresults, including substitution of dispense actions for aspirationactions as previously discussed with reference to storage channels.

The embodiments described herein are referred in the specification as“one embodiment,” “an embodiment,” “an example embodiment,” etc. Thesereferences indicate that the embodiment(s) described can include aparticular feature, structure, or characteristic, but every embodimentdoes not necessarily include every described feature, structure, orcharacteristic. Further, when a particular feature, structure, orcharacteristic is described in connection with an embodiment, suchfeature, structure, or characteristic in may also be used in connectionwith other embodiments whether or not explicitly described.

This disclosure mentions certain other documents incorporated byreference. Where such documents conflict with the express disclosure ofthis document, this document shall control.

I claim:
 1. An analyzer for analyzing a sample, the analyzer comprising:a pump; a valve fluidically coupled to the pump; a port fluidicallycoupled to the valve and configured to receive a sample; a first storagechannel fluidically coupled to the valve, the first storage channelconsisting of an elongated lumen, a first end, and a second end; aplurality of first assay packets stored in the first storage channel,the plurality of first assay packets including prealiquoted reagents andsubstantially immiscible bounding slugs, the prealiquoted reagentsseparated by the substantially immiscible bounding slugs; a detectorconfigured to detect a signal; and a controller operatively coupled tothe pump, to the valve, and to the detector, the controller programmedto operate the pump and the valve to remove an assay packet of theplurality of first assay packets from the first storage channel, tocombine a received sample with the removed assay packet to form a testpacket, and programmed to receive the signal of a reaction in the testpacket from the detector, wherein each of the first end and the secondend directly contacts the valve, wherein the lumen is in fluidcommunication with the valve through the first end and through thesecond end.
 2. The analyzer of claim 1 wherein the controller is furtherprogrammed to operate the valve and the pump to form the plurality offirst assay packets.
 3. The analyzer of claim 2, wherein the port isconfigured to engage with a sampling device, and wherein the controlleris further programmed to load a sample from a sampling device when thesampling device is engaged with the port.
 4. The analyzer of claim 3,wherein the controller is further programmed to form the test packet bycombining a portion of the loaded sample with the assay packet.
 5. Theanalyzer of claim 1, further comprising a vent fluidically coupled tothe valve, wherein the valve includes a first common channel and asecond common channel, the first common channel fluidically coupled tothe pump, and the second common channel fluidically coupled to the vent,and wherein the valve is positionable to connect the first commonchannel to the first end and the second common channel to the secondend.
 6. The analyzer of claim 1, wherein the valve includes a stator anda rotor, the stator defining a substantially cylindrical cavity and therotor disposed in the cavity, the rotor incorporating first driveelements.
 7. The analyzer of claim 6, wherein the valve further includesa bearing disposed between the rotor and the stator, wherein the statorincludes second drive elements, wherein the first and the second driveelements include one or more of magnets, coils, or pole pieces, andwherein the controller operates the valve by selectively activating oneor more of the first and the second drive elements.
 8. The analyzer ofclaim 6, wherein the rotor includes a circumferential surface separatedfrom the cylindrical wall of the cavity by a gap, the gap configured toconfine an isolation fluid.
 9. The analyzer of claim 8, wherein thecircumferential surface and the cylindrical wall each includefluoropolymer materials, and wherein the isolation fluid includes afluorocarbon liquid capable of wetting the fluoropolymer materials. 10.The analyzer of claim 1, further comprising a second storage channelfluidically coupled to the valve and a plurality of second assay packetsstored in the second storage channel.
 11. The analyzer of claim 1,further comprising a sampling device including: a tube defining a flowchannel having a first channel end and a second channel end; aseparation medium disposed in the flow channel; a collection chamberdisposed intermediate the first channel end and the separation medium; afirst connection disposed on the first channel end; and a secondconnection disposed on the second channel end, wherein the firstconnection is disposed coaxially to the second connection.
 12. Theanalyzer of claim 11, wherein the sampling device further comprises asample treatment material disposed within the tube.
 13. The analyzer ofclaim 12, wherein the sampling device further comprises a flow isolatordisposed between the collection chamber and the separation medium. 14.The analyzer of claim 13, wherein the flow isolator includes a sectionof the flow channel of larger diameter than the collection chamber or asection of the flow channel with a hydrophobic surface.
 15. The analyzerof claim 1, wherein the first storage channel content consists ofnon-sample components.